Drp1-mediated mitochondrial fission promotes pulmonary fibrosis progression through the regulation of lipid metabolic reprogramming by ROS/HIF-1α
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved..
OBJECTIVE: To confirm the mechanism of dynamic-related protein 1 (Drp1)-mediated mitochondrial fission through ROS/HIF-1α-mediated regulation of lipid metabolic reprogramming in the progression of pulmonary fibrosis (PF).
METHODS: A mouse model of PF was established by intratracheal instillation of bleomycin (BLM) (2.5 mg/kg). A PF cell model was constructed by stimulating MRC-5 cells with TGF-β (10 ng/mL). Pathological changes in the lung tissue and related protein levels were observed via tissue staining. The indicators related to lipid oxidation were detected by a kit, and lipid production was confirmed through oil red O staining. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). RT-qPCR, Western blotting and immunofluorescence staining were used to detect the expression of genes and proteins related to the disease. We used CCK-8 and EdU staining to confirm cell proliferation, flow cytometry was used to confirm apoptosis and ROS levels, α-SMA expression was detected by immunofluorescence staining, and mitochondria were observed by MitoTracker staining.
RESULTS: The BLM induced lung tissue structure and alveolar wall thickening in mice. Mitochondrial fission was observed in MRC-5 cells induced by TGF-β, which led to increased cell proliferation; decreased apoptosis; increased expression of collagen, α-SMA and Drp1; and increased lipid oxidation and inflammation. Treatment with the Drp1 inhibitor mdivi-1 or transfection with si-Drp1 attenuated the induction of BLM and TGF-β. For lipid metabolism, lipid droplets were formed in BLM-induced lung tissue and in TGF-β-induced cells, fatty acid oxidation genes and lipogenesis-related genes were upregulated, ROS levels in cells were increased, and the expression of HIF-1α was upregulated. Mdivi-1 treatment reversed TGF-β induction, while H2O2 treatment or OE-HIF-1α transfection reversed the effect of mdivi-1.
CONCLUSION: In PF, inhibition of Drp1 can prevent mitochondrial fission in fibroblasts and regulate lipid metabolism reprogramming through ROS/HIF-1α; thus, fibroblast activation was inhibited, alleviating the progression of PF.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:117 |
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| Enthalten in: |
Cellular signalling - 117(2024) vom: 02. März, Seite 111075 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tong, Zhongkai [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.03.2024 Date Revised 22.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.cellsig.2024.111075 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368191982 |
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| 245 | 1 | 0 | |a Drp1-mediated mitochondrial fission promotes pulmonary fibrosis progression through the regulation of lipid metabolic reprogramming by ROS/HIF-1α |
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| 500 | |a Date Revised 22.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a OBJECTIVE: To confirm the mechanism of dynamic-related protein 1 (Drp1)-mediated mitochondrial fission through ROS/HIF-1α-mediated regulation of lipid metabolic reprogramming in the progression of pulmonary fibrosis (PF) | ||
| 520 | |a METHODS: A mouse model of PF was established by intratracheal instillation of bleomycin (BLM) (2.5 mg/kg). A PF cell model was constructed by stimulating MRC-5 cells with TGF-β (10 ng/mL). Pathological changes in the lung tissue and related protein levels were observed via tissue staining. The indicators related to lipid oxidation were detected by a kit, and lipid production was confirmed through oil red O staining. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). RT-qPCR, Western blotting and immunofluorescence staining were used to detect the expression of genes and proteins related to the disease. We used CCK-8 and EdU staining to confirm cell proliferation, flow cytometry was used to confirm apoptosis and ROS levels, α-SMA expression was detected by immunofluorescence staining, and mitochondria were observed by MitoTracker staining | ||
| 520 | |a RESULTS: The BLM induced lung tissue structure and alveolar wall thickening in mice. Mitochondrial fission was observed in MRC-5 cells induced by TGF-β, which led to increased cell proliferation; decreased apoptosis; increased expression of collagen, α-SMA and Drp1; and increased lipid oxidation and inflammation. Treatment with the Drp1 inhibitor mdivi-1 or transfection with si-Drp1 attenuated the induction of BLM and TGF-β. For lipid metabolism, lipid droplets were formed in BLM-induced lung tissue and in TGF-β-induced cells, fatty acid oxidation genes and lipogenesis-related genes were upregulated, ROS levels in cells were increased, and the expression of HIF-1α was upregulated. Mdivi-1 treatment reversed TGF-β induction, while H2O2 treatment or OE-HIF-1α transfection reversed the effect of mdivi-1 | ||
| 520 | |a CONCLUSION: In PF, inhibition of Drp1 can prevent mitochondrial fission in fibroblasts and regulate lipid metabolism reprogramming through ROS/HIF-1α; thus, fibroblast activation was inhibited, alleviating the progression of PF | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Drp1 | |
| 650 | 4 | |a HIF-1α | |
| 650 | 4 | |a Lipid metabolism | |
| 650 | 4 | |a Mitochondrial fission | |
| 650 | 4 | |a Pulmonary fibrosis | |
| 650 | 4 | |a ROS | |
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| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a Transforming Growth Factor beta |2 NLM | |
| 700 | 1 | |a Du, Xuekui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Jing, Fangxue |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, JiangPo |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Yingying |e verfasserin |4 aut | |
| 700 | 1 | |a Lou, Saiyun |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qiong |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Zhaoxing |e verfasserin |4 aut | |
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